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    Clinical Trial Results:
    Safety and Immunogenicity of Different Dosages of High-Dose Quadrivalent Influenza Vaccine in Children 6 Months to 17 Years of Age

    Summary
    EudraCT number
    2018-005026-39
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    16 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Apr 2020
    First version publication date
    26 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    QHD04
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03698279
    WHO universal trial number (UTN)
    U1111-1189-3713
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc.
    Sponsor organisation address
    Discovery Drive, Swiftwater, United States, PA 18370-0187
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002359-PIP01-18
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safety: To describe the safety of each dosage of high-dose quadrivalent influenza vaccine (QIV-HD) used in the study during the 28 days following each vaccination, and serious adverse events (SAEs) (including adverse events of special interest) throughout the study. Immunogenicity: To describe the antibody response induced by each dosage of QIV-HD used in the study compared with unadjuvanted standard-dose quadrivalent influenza vaccine (QIV-SD) by haemagglutination inhibition (HAI) measurement method. To describe the antibody response induced by each dosage of QIV-HD used in the study compared with unadjuvanted QIV-SD by virus seroneutralisation (SN) measurement method. To describe the antibody response induced by the highest acceptable dosage of QIV-HD compared with adjuvanted trivalent influenza vaccine (TIV) by HAI and virus SN measurement methods.
    Protection of trial subjects
    Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment were also available on site in case of any immediate allergic reactions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 639
    Country: Number of subjects enrolled
    Canada: 26
    Worldwide total number of subjects
    665
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    118
    Children (2-11 years)
    473
    Adolescents (12-17 years)
    74
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 16 centres in United States (US) and Canada from 09 October 2018 to 16 October 2019.

    Pre-assignment
    Screening details
    A total of 665 subjects were enrolled in the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years)
    Arm description
    Subjects from US (aged 6 months to 17 years) received 30 microgram (µg) QIV-HD, intramuscularly (IM).
    Arm type
    Experimental

    Investigational medicinal product name
    High-Dose Quadrivalent Influenza Vaccine (QIV-HD) (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 injection at Day 0. Subjects for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.

    Arm title
    Group 2: QIV-HD 45 µg (US: 6 months to 17 years)
    Arm description
    Subjects from US (aged 6 months to 17 years) received 45 µg QIV-HD, IM.
    Arm type
    Experimental

    Investigational medicinal product name
    High-Dose Quadrivalent Influenza Vaccine, (QIV-HD) (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 injection at Day 0. Subjects for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.

    Arm title
    Group 3: QIV-HD, 60 µg (US: 6 months to 17 years)
    Arm description
    Subjects from US (aged 6 months to 17 years) received 60 µg QIV-HD, IM.
    Arm type
    Experimental

    Investigational medicinal product name
    High-Dose Quadrivalent Influenza Vaccine (QIV-HD) (split-virion, purified)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 injection at Day 0. Subjects for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.

    Arm title
    Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years)
    Arm description
    Pooled arm consisted of subjects who were from US aged 6 months to 17 years, randomised to Groups 1, 2 and 3 and received 15 µg QIV-SD, IM.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fluarix Quadrivalent Influenza vaccine (Unadjuvanted QIV-SD)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 injection at Day 0. Subjects for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.

    Arm title
    Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months)
    Arm description
    Subjects from Canada (aged 6 to <24 months) received 60 µg QIV-HD, IM.
    Arm type
    Experimental

    Investigational medicinal product name
    High-Dose Quadrivalent Influenza Vaccine (QIV-HD) (split-virion, purified)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 injection at Day 0. Subjects for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.

    Arm title
    Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Arm description
    Subjects from Canada (aged 6 to <24 months) received 7.5 µg adjuvanted TIV, IM.
    Arm type
    Active comparator

    Investigational medicinal product name
    FLUAD Pediatric (adjuvanted TIV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 injection at Day 0. Subjects for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28.

    Number of subjects in period 1
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Started
    124
    122
    159
    234
    13
    13
    Safety analysis set population (SafAS)
    122
    121
    158
    234
    13
    13
    Completed
    119
    120
    152
    228
    13
    13
    Not completed
    5
    2
    7
    6
    0
    0
         Withdrawal by parent/guardian
    1
    1
    1
    1
    -
    -
         Protocol deviation
    1
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    3
    1
    4
    5
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 30 microgram (µg) QIV-HD, intramuscularly (IM).

    Reporting group title
    Group 2: QIV-HD 45 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 45 µg QIV-HD, IM.

    Reporting group title
    Group 3: QIV-HD, 60 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 60 µg QIV-HD, IM.

    Reporting group title
    Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years)
    Reporting group description
    Pooled arm consisted of subjects who were from US aged 6 months to 17 years, randomised to Groups 1, 2 and 3 and received 15 µg QIV-SD, IM.

    Reporting group title
    Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months)
    Reporting group description
    Subjects from Canada (aged 6 to <24 months) received 60 µg QIV-HD, IM.

    Reporting group title
    Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Reporting group description
    Subjects from Canada (aged 6 to <24 months) received 7.5 µg adjuvanted TIV, IM.

    Reporting group values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months) Total
    Number of subjects
    124 122 159 234 13 13 665
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.8 ± 3.91 6.1 ± 4.30 5.2 ± 4.22 5.1 ± 4.02 0.8 ± 0.19 1.0 ± 0.28 -
    Gender categorical
    Units: Subjects
        Female
    51 61 82 114 4 6 318
        Male
    73 61 77 120 9 7 347
    Race
    Units: Subjects
        American Indian or Alaska Native
    2 0 0 2 0 0 4
        Asian
    1 2 0 3 0 0 6
        Black or African American
    22 28 40 58 2 0 150
        Native Hawaiian or Other Pacific Islander
    0 3 2 5 0 1 11
        White
    92 81 108 157 9 11 458
        Multiple
    4 3 8 7 2 1 25
        Not Reported
    3 5 1 2 0 0 11

    End points

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    End points reporting groups
    Reporting group title
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 30 microgram (µg) QIV-HD, intramuscularly (IM).

    Reporting group title
    Group 2: QIV-HD 45 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 45 µg QIV-HD, IM.

    Reporting group title
    Group 3: QIV-HD, 60 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 60 µg QIV-HD, IM.

    Reporting group title
    Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years)
    Reporting group description
    Pooled arm consisted of subjects who were from US aged 6 months to 17 years, randomised to Groups 1, 2 and 3 and received 15 µg QIV-SD, IM.

    Reporting group title
    Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months)
    Reporting group description
    Subjects from Canada (aged 6 to <24 months) received 60 µg QIV-HD, IM.

    Reporting group title
    Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Reporting group description
    Subjects from Canada (aged 6 to <24 months) received 7.5 µg adjuvanted TIV, IM.

    Subject analysis set title
    Group 4a: QIV-SD, 15 µg, (US: 6 months to 17 years)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects from US (aged 6 months to 17 years) received 15 µg QIV-SD, IM and were restricted for comparison to relevant experimental study group QIV-HD 30 µg.

    Subject analysis set title
    Group 4b: QIV-SD, 15 µg, (US: 6 months to 17 years)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects from US (aged 6 months to 17 years) received 15 µg QIV-SD, IM and were restricted for comparison to relevant experimental study group QIV-HD 45 µg.

    Subject analysis set title
    Group 4c: QIV-SD, 15 µg, (US: 6 months to 17 years)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects from US (aged 6 months to 17 years) received 15 µg QIV-SD, IM and were restricted for comparison to relevant experimental study group QIV-HD 60 µg.

    Primary: Number of Subjects With Immediate Unsolicited Adverse Events After any Vaccination

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    End point title
    Number of Subjects With Immediate Unsolicited Adverse Events After any Vaccination [1]
    End point description
    An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the case report book (CRB) in terms of diagnosis and/or onset window post-vaccination. Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. All subjects were observed for 30 minutes after vaccination, and any unsolicited systemic AEs occurred during that time were recorded as immediate unsolicited AEs in the CRB. Analysis was performed on SafAS which included subjects who had received at least one dose of the study vaccines.
    End point type
    Primary
    End point timeframe
    Within 30 minutes after any vaccination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    122
    121
    158
    234
    13
    13
    Units: subjects
        number (not applicable)
    0
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Unsolicited Adverse Events After any Vaccination

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    End point title
    Number of Subjects With Unsolicited Adverse Events After any Vaccination [2]
    End point description
    An unsolicited AE was an observed AE that does not fulfill the conditions prelisted in the CRB in terms of diagnosis and/or onset window post-vaccination. Unsolicited AEs included both serious and non-serious unsolicited AEs. An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. Adverse reactions (ARs) were AEs related to vaccination. An injection site reaction was an AR at and around the injection site. Systemic AEs were all AEs that were not injection or administration site reactions. Analysis was performed on the SafAS population.
    End point type
    Primary
    End point timeframe
    Within 28 days after any vaccination
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    122
    121
    158
    234
    13
    13
    Units: subjects
    number (not applicable)
        Unsolicited AE
    46
    46
    53
    80
    11
    12
        Unsolicited non-serious AR
    4
    8
    8
    10
    1
    3
        Unsolicited non-serious injection site AR
    0
    3
    0
    0
    0
    1
        Unsolicited non-serious systemic AE
    46
    45
    52
    80
    11
    12
        Unsolicited non-serious systemic AR
    4
    5
    8
    10
    1
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Serious Adverse Events (SAEs) After any Vaccination

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    End point title
    Number of Subjects With Serious Adverse Events (SAEs) After any Vaccination [3]
    End point description
    An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. An SAE which caused death of the subject was considered as fatal SAE. Adverse events of special interest (AESIs) were captured as SAEs which included new onset of Guillain-Barré syndrome, encephalitis/myelitis (including transverse myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. Analysis was performed on the SafAS population.
    End point type
    Primary
    End point timeframe
    From Day 0 up to 6 months post-vaccination
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    122
    121
    158
    234
    13
    13
    Units: subjects
    number (not applicable)
        SAE
    0
    0
    2
    0
    0
    1
        Fatal SAE
    0
    0
    0
    0
    0
    0
        AESI
    0
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects Achieving Seroconversion Against Antigens Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine

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    End point title
    Number of Subjects Achieving Seroconversion Against Antigens Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine [4] [5]
    End point description
    Anti-influenza antibodies were measured by HAI assay for strains A/H1N1, A/H3N2, B/Victoria lineage and B/Yamagata lineage. Seroconversion was defined as either a HAI titer <10 (1/dilution) at Day 0 and post-vaccination titer greater than or equal to (>=) 40 (1/dilution) at Day 28, or HAI titer >=10 (1/dilution) at Day 0 and >=4-fold increase in HAI titer (1/dilution) at Day 28. Due to complex study design and analysis of dose formulation and age groups, subjects in QIV-HD 30 µg and QIV-HD 45 µg dose formulations groups from age cohort 9 through 17 years old were randomised and shared a matching age group with QIV-SD control group. Hence, those subjects were counted more than once in QIV-SD arms for different dose levels. Analysis was performed on immunogenicity analysis set (IAS) population which included randomised subjects who received 1 dose/2 doses of study vaccine and had a post-vaccination blood sample. Here, ‘n’=subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 28 post any vaccination
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since the comparison assessment was performed based on the strain and dosages, the inferential statistical analysis and the percentage of comparison against the pooled arm data is not presented.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months) Group 4a: QIV-SD, 15 µg, (US: 6 months to 17 years) Group 4b: QIV-SD, 15 µg, (US: 6 months to 17 years) Group 4c: QIV-SD, 15 µg, (US: 6 months to 17 years)
    Number of subjects analysed
    118
    115
    156
    13
    13
    40
    41
    157
    Units: subjects
    number (not applicable)
        A/H1N1 (n = 110, 112, 141, 11, 12, 39, 41, 148)
    72
    71
    107
    8
    11
    26
    24
    98
        A/H3N2 (n = 109, 111, 140, 11, 12, 38, 41, 146)
    63
    79
    102
    8
    12
    18
    20
    71
        B/Victoria (n= 110, 111, 141, 11, 12, 39, 41, 148)
    84
    94
    117
    6
    12
    28
    30
    111
        B/Yamagata (n= 110, 109, 141, 11, 12, 38, 41, 147)
    79
    85
    120
    8
    1
    26
    31
    117
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine [6] [7]
    End point description
    GMTs of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. Due to complex study design and analysis of dose formulation and age groups, subjects in QIV-HD 30 µg & QIV-HD 45 µg dose formulations groups from age cohort 9 through 17 years old were randomised and shared a matching age group with QIV-SD control group. Hence, those subjects were counted more than once in QIV-SD arms for different dose levels.Analysis was performed on IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 28 post any vaccination
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since the comparison assessment was performed based on the strain and dosages, the inferential statistical analysis and the percentage of comparison against the pooled arm data is not presented.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months) Group 4a: QIV-SD, 15 µg, (US: 6 months to 17 years) Group 4b: QIV-SD, 15 µg, (US: 6 months to 17 years) Group 4c: QIV-SD, 15 µg, (US: 6 months to 17 years)
    Number of subjects analysed
    118
    115
    156
    13
    13
    40
    41
    157
    Units: titers (1/dilution)
    geometric mean (confidence interval 95%)
        A/H1N1 (n = 116, 114, 145, 13, 12, 40, 41, 151)
    673 (525 to 863)
    676 (524 to 873)
    834 (674 to 1033)
    59.7 (27.0 to 132)
    604 (261 to 1398)
    698 (419 to 1161)
    791 (480 to 1303)
    618 (461 to 830)
        A/H3N2 (n = 116, 113, 144, 13, 12, 39, 41, 151)
    518 (399 to 671)
    781 (600 to 1017)
    770 (604 to 982)
    66.4 (33.0 to 133)
    604 (386 to 946)
    314 (184 to 538)
    441 (264 to 738)
    307 (239 to 395)
        B/Victoria (n= 116, 113, 145, 13, 12, 40, 41, 151)
    378 (296 to 483)
    432 (334 to 560)
    494 (400 to 612)
    56.6 (26.2 to 122)
    1244 (767 to 2016)
    296 (194 to 452)
    468 (302 to 726)
    310 (246 to 390)
        B/Yamagata (n= 116, 112, 144, 13, 12, 39, 41, 151)
    723 (582 to 899)
    720 (556 to 932)
    877 (722 to 1066)
    75.8 (38.9 to 148)
    21.8 (12.3 to 38.6)
    706 (474 to 1050)
    727 (501 to 1054)
    580 (466 to 721)
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine

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    End point title
    Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine [8]
    End point description
    GMTs of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. GMTRs were calculated as the ratio of GMTs post- vaccination and pre-vaccination. Analysis was performed on IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination), Day 28 (post any vaccination)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    118
    115
    156
    227
    13
    13
    Units: ratio
    geometric mean (confidence interval 95%)
        A/H1N1: Day 28/Day 0 (n = 110,112,141,217,11,12)
    8.55 (6.39 to 11.4)
    10.0 (7.31 to 13.7)
    16.3 (12.1 to 22.0)
    10.1 (8.07 to 12.8)
    1.41 (0.878 to 2.28)
    4.76 (2.72 to 8.32)
        A/H3N2: Day 28/Day 0 (n = 109,111,140,214,11,12)
    6.42 (4.95 to 8.34)
    9.35 (7.15 to 12.2)
    10.3 (8.09 to 13.0)
    4.61 (3.90 to 5.45)
    1.41 (1.00 to 2.00)
    15.5 (8.89 to 27.2)
        B/Victoria: Day 28/Day 0 (n=110,111,141,217,11,12)
    10.7 (8.31 to 13.7)
    11.7 (9.30 to 14.7)
    16.7 (13.2 to 21.0)
    11.0 (9.24 to 13.2)
    1.37 (0.949 to 1.98)
    11.0 (6.28 to 19.2)
        B/Yamagata: Day 28/Day 0 (n=110,109,141,215,11,12)
    9.28 (7.10 to 12.1)
    11.4 (8.83 to 14.7)
    18.1 (13.9 to 23.6)
    9.77 (8.15 to 11.7)
    1.71 (1.07 to 2.73)
    0.944 (0.785 to 1.13)
    No statistical analyses for this end point

    Primary: Number of Subjects With Neutralisation Antibody Titers >=40 (1/Dilution) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine

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    End point title
    Number of Subjects With Neutralisation Antibody Titers >=40 (1/Dilution) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine [9]
    End point description
    GMT was measured for each influenza strain using HAI assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage. Analysis was performed on the IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 28 post any vaccination
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    118
    115
    156
    227
    13
    13
    Units: subjects
    number (not applicable)
        A/H1N1: Day 28 (n = 116, 114, 145, 221, 13, 12)
    113
    110
    142
    198
    0
    7
        A/H3N2: Day 28 (n = 116, 113, 144, 220, 13, 12)
    111
    110
    139
    198
    0
    9
        B/Victoria: Day 28 (n = 116, 113, 145, 221, 13,12)
    112
    108
    140
    202
    0
    9
        B/Yamagata: Day 28 (n = 116, 112, 144, 220, 13,12)
    115
    109
    142
    215
    1
    1
    No statistical analyses for this end point

    Primary: Geometric Mean Titers of Influenza Antibodies (Seroneutralisation Assay Method) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine

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    End point title
    Geometric Mean Titers of Influenza Antibodies (Seroneutralisation Assay Method) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine [10]
    End point description
    GMT was measured for each influenza strain using SN assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage. Analysis was performed on the IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 28 post any vaccination
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    118
    115
    156
    227
    13
    13
    Units: titers (1/dilution)
    geometric mean (confidence interval 95%)
        A/H1N1: (n = 112, 112, 147, 216, 12, 11)
    6589 (4959 to 8754)
    6213 (4672 to 8264)
    7045 (5514 to 9001)
    4948 (3676 to 6659)
    33.8 (14.8 to 76.9)
    234 (32.0 to 1708)
        A/H3N2: (n = 113, 111, 142, 215, 11, 11)
    641 (515 to 798)
    921 (718 to 1181)
    884 (717 to 1091)
    411 (347 to 487)
    54.4 (35.3 to 83.9)
    188 (119 to 298)
        B/Victoria: (n=113, 112, 146, 216, 12, 11)
    500 (375 to 667)
    605 (444 to 825)
    628 (484 to 815)
    378 (302 to 472)
    6.05 (4.54 to 8.07)
    57.9 (39.5 to 84.9)
        B/Yamagata: (n=112, 112, 146, 214, 12, 11)
    1147 (893 to 1474)
    1159 (865 to 1552)
    1254 (1015 to 1549)
    846 (698 to 1026)
    17.6 (11.1 to 27.8)
    17.4 (9.86 to 30.6)
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios of Influenza Antibodies (Seroneutralisation Assay Method) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine

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    End point title
    Geometric Mean Titer Ratios of Influenza Antibodies (Seroneutralisation Assay Method) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine [11]
    End point description
    GMTRs of anti-influenza antibodies were measured using SN assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage and B/Yamagata lineage. GMTRs were calculated as the ratio of GMTs post vaccination and pre-vaccination. Analysis was performed on IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination), Day 28 (post any vaccination)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    118
    115
    156
    227
    13
    13
    Units: ratio
    geometric mean (confidence interval 95%)
        A/H1N1: Day 28/Day 0 (n = 103,105,138,206,10,11)
    11.3 (7.67 to 16.7)
    18.8 (12.1 to 29.4)
    29.1 (19.6 to 43.2)
    14.5 (11.0 to 19.0)
    2.38 (0.663 to 8.53)
    7.12 (3.00 to 16.9)
        A/H3N2: Day 28/Day 0 (n=101,101,134,206,10,11)
    3.60 (2.98 to 4.34)
    5.20 (4.11 to 6.59)
    5.54 (4.58 to 6.70)
    2.66 (2.34 to 3.04)
    1.04 (0.629 to 1.72)
    2.81 (1.65 to 4.78)
        B/Victoria: Day 28/Day 0 (n=102,105,137,205,10,11)
    12.4 (9.51 to 16.2)
    15.4 (11.9 to 20.0)
    19.9 (15.1 to 26.3)
    12.7 (10.4 to 15.4)
    1.03 (0.612 to 1.74)
    10.5 (6.73 to 16.3)
        B/Yamagata: Day 28/Day 0 (n=101,103,137,204,10,11)
    9.75 (7.50 to 12.7)
    11.5 (9.06 to 14.7)
    14.1 (11.1 to 17.8)
    8.49 (7.18 to 10.0)
    1.16 (0.604 to 2.24)
    1.10 (0.760 to 1.61)
    No statistical analyses for this end point

    Primary: Number of Subjects With Neutralisation Antibody Titers above Pre-Defined Thresholds

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    End point title
    Number of Subjects With Neutralisation Antibody Titers above Pre-Defined Thresholds [12]
    End point description
    Neutralising Antibody titer was measured for each influenza strain with SN assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage at pre-defined thresholds of >=20, >=40 and >=80 (1/dilution). Analysis was performed on the IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 28 post any vaccination
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    118
    115
    156
    227
    13
    13
    Units: subjects
    number (not applicable)
        A/H1N1: >=20 (1/dil) (n=112,112,147,216,13,11)
    112
    112
    147
    208
    13
    11
        A/H1N1: >=40 (1/dil) (n=112,112,147,216,13,11)
    112
    112
    147
    202
    12
    11
        A/H1N1: >=80 (1/dil) (n=112,112,147,216,13,11)
    111
    111
    146
    201
    11
    11
        A/H3N2: >=20 (1/dil) (n=113,111,142,215,13,11)
    113
    111
    142
    214
    13
    11
        A/H3N2: >=40 (1/dil) (n=113,111,142,215,13,11)
    111
    111
    141
    208
    13
    11
        A/H3N2: >=80 (1/dil) (n=113,111,142,215,13,11)
    107
    107
    138
    190
    11
    11
        B/Victoria: >=20 (1/dil) (n=113,112,146,216,13,11)
    110
    108
    143
    201
    9
    11
        B/Victoria: >=40 (1/dil) (n=113,112,146,216,13,11)
    108
    104
    136
    195
    8
    11
        B/Victoria: >=80 (1/dil) (n=113,112,146,216,13,11)
    99
    99
    128
    181
    6
    11
        B/Yamagata: >=20 (1/dil) (n=112,112,146,214,13,11)
    111
    112
    146
    213
    13
    10
        B/Yamagata: >=40 (1/dil) (n=112,112,146,214,13,11)
    111
    108
    145
    208
    9
    6
        B/Yamagata: >=80 (1/dil) (n=112,112,146,214,13,11)
    110
    103
    140
    201
    7
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Two-Fold and Four-Fold Increase in Neutralisation Antibody Titer at Day 28

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    End point title
    Number of Subjects With Two-Fold and Four-Fold Increase in Neutralisation Antibody Titer at Day 28 [13]
    End point description
    Neutralising Antibody titer was measured for each influenza strain with SN method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage. 2-fold and 4-fold rise was defined as the computed value = post-vaccination computed value/pre-vaccination computed value. Analysis was performed on the IAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 28 post any vaccination
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    118
    115
    156
    227
    13
    13
    Units: subjects
    number (not applicable)
        2-Fold Rise: A/H1N1 (n=103,105,138,206,10,11)
    80
    83
    118
    168
    6
    10
        4-Fold Rise: A/H1N1 (n=103,105,138,206,10,11)
    65
    70
    104
    141
    5
    9
        2-Fold Rise: A/H3N2 (n = 101,101,134, 206,10,11)
    69
    77
    110
    111
    2
    7
        4-Fold Rise: A/H3N2 (n = 101,101,134, 206,10,11)
    44
    51
    72
    61
    0
    3
        2-Fold Rise: B/Victoria (n =102,105,137,205,10,11)
    95
    99
    131
    185
    2
    11
        4-Fold Rise: B/Victoria (n =102,105,137,205,10,11)
    80
    88
    113
    158
    0
    10
        2-Fold Rise: B/Yamagata (n =101,103,137,204,10,11)
    84
    95
    127
    187
    4
    3
        4-Fold Rise: B/Yamagata (n =101,103,137,204,10,11)
    71
    81
    109
    142
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Solicited Injection Site Reactions After any Vaccination

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    End point title
    Number of Subjects With Solicited Injection Site Reactions After any Vaccination [14]
    End point description
    A solicited reaction was an "expected' adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted (i.e., solicited) in the CRB and considered as related to the administered vaccination. Solicited injection site reactions included tenderness/pain, erythema, swelling, induration and bruising. Analysis was performed on the SafAS population. Here, ‘Number of subjects analysed’= subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Within 7 days after any vaccination
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    122
    119
    158
    232
    13
    13
    Units: subjects
    number (not applicable)
        Injection site tenderness/pain
    81
    84
    100
    116
    6
    5
        Injection site erythema
    31
    30
    40
    48
    5
    8
        Injection site swelling
    17
    15
    34
    23
    2
    2
        Injection site induration
    21
    18
    26
    22
    4
    5
        Injection site bruising
    10
    10
    13
    16
    1
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Solicited Systemic Reactions After any Vaccination: Subjects Aged 6 Months to <36 Months

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    End point title
    Number of Subjects With Solicited Systemic Reactions After any Vaccination: Subjects Aged 6 Months to <36 Months [15]
    End point description
    A solicited reaction was an "expected' adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted (i.e., solicited) in the CRB and considered as related to the administered vaccination. Solicited systemic reactions included fever, vomiting, crying abnormal, drowsiness, appetite loss and irritability. Analysis was performed on the SafAS population. Here, ‘n’= subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Within 7 days after any vaccination
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Number of subjects analysed
    122
    121
    158
    234
    13
    13
    Units: subjects
    number (not applicable)
        Fever (n= 122, 120, 158, 231, 13, 13)
    5
    6
    15
    11
    5
    6
        Vomiting (n = 29, 30, 54, 74, 13, 13)
    1
    2
    7
    11
    5
    7
        Crying abnormal (n = 29, 30, 54, 74, 13, 13)
    11
    9
    10
    20
    6
    9
        Drowsiness (n = 29, 30, 54, 74, 13, 13)
    14
    11
    12
    17
    5
    5
        Appetite lost (n = 29, 30, 54, 74, 13, 13)
    6
    10
    15
    20
    11
    11
        Irritability (n = 29, 30, 54, 74, 13, 13)
    14
    13
    18
    23
    6
    12
    No statistical analyses for this end point

    Primary: Number of Subjects With Solicited Systemic Reactions After any Vaccination: Subjects Aged Greater Than (>) 36 Months

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    End point title
    Number of Subjects With Solicited Systemic Reactions After any Vaccination: Subjects Aged Greater Than (>) 36 Months [16] [17]
    End point description
    A solicited reaction was an "expected' adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted (i.e., solicited) in the CRB and considered as related to the administered vaccination. Solicited systemic reactions included: headache, malaise, myalgia and shivering. Analysis was performed on the SafAS population. Here, ‘Number of subjects analysed’= subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Within 7 days after any vaccination
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Systemic reactions data for Subjects Aged >36 months was planned to be collected and analysed for Groups 1-4 only.
    End point values
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years)
    Number of subjects analysed
    93
    89
    104
    158
    Units: subjects
    number (not applicable)
        Headache
    18
    18
    22
    21
        Malaise
    16
    28
    27
    32
        Myalgia
    29
    30
    32
    42
        Shivering
    1
    8
    8
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from Day 0 (post-vaccination) up to 28 days after last vaccination. Solicited Reaction (SR) data were collected up to Day 7 after any vaccination. SAE data were collected throughout the study (up to 180 days after last vaccination).
    Adverse event reporting additional description
    A SR was an AE that was prelisted (i.e., solicited) in the CRB and considered to be related to vaccination (adverse drug reaction). An unsolicited AE was an observed AE that did not fulfill the conditions prelisted (i.e., solicited) in the CRB in terms of diagnosis and/or onset window post-vaccination. Analysis was performed on SafAS population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 30 µg QIV-HD, IM.

    Reporting group title
    Group 2: QIV-HD 45 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 45 µg QIV-HD, IM.

    Reporting group title
    Group 3: QIV-HD, 60 µg (US: 6 months to 17 years)
    Reporting group description
    Subjects from US (aged 6 months to 17 years) received 60 µg QIV-HD, IM.

    Reporting group title
    Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years)
    Reporting group description
    Pooled arm consisted of subjects who were from US aged 6 months to 17 years, randomised to Group 1, 2 and 3 and received 15 µg QIV-SD, IM.

    Reporting group title
    Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months)
    Reporting group description
    Subjects form Canada (aged 6 to <24 months) received 60 µg QIV-HD, IM.

    Reporting group title
    Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Reporting group description
    Subjects from Canada (aged 6 to <24 months) received 7.5 µg adjuvanted TIV, IM.

    Serious adverse events
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    2 / 158 (1.27%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Febrile Convulsion
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    1 / 158 (0.63%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Ear Infection
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    1 / 158 (0.63%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1: QIV-HD 30 µg (US: 6 months to 17 years) Group 2: QIV-HD 45 µg (US: 6 months to 17 years) Group 3: QIV-HD, 60 µg (US: 6 months to 17 years) Group 4: Pooled QIV-SD, 15 µg (US: 6 months to 17 years) Group 5: QIV-HD, 60 µg (Canada: 6 to <24 months) Group 6: Adjuvanted TIV (Canada: 6 to <24 months)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 122 (82.79%)
    100 / 121 (82.64%)
    118 / 158 (74.68%)
    165 / 234 (70.51%)
    13 / 13 (100.00%)
    13 / 13 (100.00%)
    Injury, poisoning and procedural complications
    Tongue Injury
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 122 (13.93%)
    19 / 121 (15.70%)
    15 / 158 (9.49%)
    30 / 234 (12.82%)
    2 / 13 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    17
    22
    17
    30
    4
    1
    Nasal Congestion
         subjects affected / exposed
    2 / 122 (1.64%)
    8 / 121 (6.61%)
    3 / 158 (1.90%)
    6 / 234 (2.56%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    8
    3
    6
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    7 / 122 (5.74%)
    6 / 121 (4.96%)
    4 / 158 (2.53%)
    13 / 234 (5.56%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    7
    6
    7
    13
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    18 / 122 (14.75%)
    19 / 121 (15.70%)
    22 / 158 (13.92%)
    22 / 234 (9.40%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    19
    19
    22
    22
    0
    0
    Somnolence
         subjects affected / exposed
    14 / 122 (11.48%)
    11 / 121 (9.09%)
    12 / 158 (7.59%)
    18 / 234 (7.69%)
    5 / 13 (38.46%)
    5 / 13 (38.46%)
         occurrences all number
    15
    12
    17
    21
    6
    7
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 122 (0.82%)
    8 / 121 (6.61%)
    8 / 158 (5.06%)
    6 / 234 (2.56%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    8
    8
    6
    0
    0
    Crying
         subjects affected / exposed
    11 / 122 (9.02%)
    9 / 121 (7.44%)
    10 / 158 (6.33%)
    20 / 234 (8.55%)
    6 / 13 (46.15%)
    9 / 13 (69.23%)
         occurrences all number
    12
    10
    12
    24
    9
    10
    Influenza Like Illness
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injection Site Bruising
         subjects affected / exposed
    10 / 122 (8.20%)
    11 / 121 (9.09%)
    13 / 158 (8.23%)
    16 / 234 (6.84%)
    1 / 13 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    10
    11
    14
    16
    1
    2
    Injection Site Erythema
         subjects affected / exposed
    31 / 122 (25.41%)
    30 / 121 (24.79%)
    40 / 158 (25.32%)
    48 / 234 (20.51%)
    5 / 13 (38.46%)
    8 / 13 (61.54%)
         occurrences all number
    32
    32
    44
    52
    7
    9
    Injection Site Induration
         subjects affected / exposed
    21 / 122 (17.21%)
    19 / 121 (15.70%)
    26 / 158 (16.46%)
    22 / 234 (9.40%)
    4 / 13 (30.77%)
    5 / 13 (38.46%)
         occurrences all number
    22
    20
    27
    24
    5
    6
    Injection Site Pain
         subjects affected / exposed
    81 / 122 (66.39%)
    84 / 121 (69.42%)
    100 / 158 (63.29%)
    116 / 234 (49.57%)
    6 / 13 (46.15%)
    5 / 13 (38.46%)
         occurrences all number
    89
    96
    111
    126
    8
    6
    Injection Site Swelling
         subjects affected / exposed
    17 / 122 (13.93%)
    15 / 121 (12.40%)
    34 / 158 (21.52%)
    23 / 234 (9.83%)
    2 / 13 (15.38%)
    2 / 13 (15.38%)
         occurrences all number
    17
    17
    35
    25
    2
    2
    Injection Site Warmth
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 121 (0.83%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Malaise
         subjects affected / exposed
    16 / 122 (13.11%)
    28 / 121 (23.14%)
    27 / 158 (17.09%)
    32 / 234 (13.68%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    16
    29
    27
    33
    0
    0
    Pyrexia
         subjects affected / exposed
    11 / 122 (9.02%)
    10 / 121 (8.26%)
    19 / 158 (12.03%)
    24 / 234 (10.26%)
    9 / 13 (69.23%)
    9 / 13 (69.23%)
         occurrences all number
    12
    11
    22
    25
    15
    17
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 121 (0.83%)
    0 / 158 (0.00%)
    1 / 234 (0.43%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Irritability
         subjects affected / exposed
    14 / 122 (11.48%)
    13 / 121 (10.74%)
    18 / 158 (11.39%)
    23 / 234 (9.83%)
    7 / 13 (53.85%)
    12 / 13 (92.31%)
         occurrences all number
    16
    15
    24
    27
    11
    19
    Sleep Terror
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 121 (1.65%)
    0 / 158 (0.00%)
    1 / 234 (0.43%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    5 / 122 (4.10%)
    5 / 121 (4.13%)
    9 / 158 (5.70%)
    12 / 234 (5.13%)
    1 / 13 (7.69%)
    4 / 13 (30.77%)
         occurrences all number
    5
    6
    10
    13
    1
    8
    Oral Mucosal Eruption
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Teething
         subjects affected / exposed
    2 / 122 (1.64%)
    1 / 121 (0.83%)
    1 / 158 (0.63%)
    1 / 234 (0.43%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    1
    2
    0
    1
    Vomiting
         subjects affected / exposed
    10 / 122 (8.20%)
    10 / 121 (8.26%)
    12 / 158 (7.59%)
    15 / 234 (6.41%)
    5 / 13 (38.46%)
    7 / 13 (53.85%)
         occurrences all number
    12
    10
    13
    16
    9
    9
    Skin and subcutaneous tissue disorders
    Dermatitis Diaper
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 121 (0.00%)
    2 / 158 (1.27%)
    3 / 234 (1.28%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    3
    3
    1
    1
    Erythema
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 121 (1.65%)
    0 / 158 (0.00%)
    1 / 234 (0.43%)
    2 / 13 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    1
    2
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    29 / 122 (23.77%)
    30 / 121 (24.79%)
    33 / 158 (20.89%)
    43 / 234 (18.38%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    33
    31
    34
    45
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    6 / 122 (4.92%)
    10 / 121 (8.26%)
    15 / 158 (9.49%)
    20 / 234 (8.55%)
    11 / 13 (84.62%)
    11 / 13 (84.62%)
         occurrences all number
    6
    11
    18
    24
    14
    14
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 121 (0.00%)
    0 / 158 (0.00%)
    0 / 234 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 121 (0.00%)
    1 / 158 (0.63%)
    0 / 234 (0.00%)
    3 / 13 (23.08%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    3
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 121 (0.83%)
    2 / 158 (1.27%)
    2 / 234 (0.85%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    2
    2
    1
    0
    Ear Infection
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 121 (0.00%)
    1 / 158 (0.63%)
    3 / 234 (1.28%)
    3 / 13 (23.08%)
    3 / 13 (23.08%)
         occurrences all number
    2
    0
    1
    3
    4
    4
    Gastroenteritis
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 121 (0.83%)
    0 / 158 (0.00%)
    1 / 234 (0.43%)
    3 / 13 (23.08%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    0
    1
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 122 (3.28%)
    4 / 121 (3.31%)
    8 / 158 (5.06%)
    5 / 234 (2.14%)
    7 / 13 (53.85%)
    7 / 13 (53.85%)
         occurrences all number
    4
    4
    8
    5
    9
    13
    Otitis Media
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 121 (0.83%)
    2 / 158 (1.27%)
    2 / 234 (0.85%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    2
    2
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 121 (0.00%)
    1 / 158 (0.63%)
    0 / 234 (0.00%)
    2 / 13 (15.38%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    1
    0
    2
    2
    Sinusitis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 121 (0.83%)
    0 / 158 (0.00%)
    1 / 234 (0.43%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 122 (4.10%)
    0 / 121 (0.00%)
    6 / 158 (3.80%)
    8 / 234 (3.42%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    5
    0
    6
    8
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2019
    Following changes were made: - Clarified exclusion criteria to describe how subjects 6 months to 8 years of age were considered as “previously influenza vaccinated” or “previously influenza unvaccinated” based on the Advisory Committee on Immunization Practices and National Advisory Committee on Immunization Guidelines. - Clarified the collection of vaccinations and medications in case of reporting a SAE. - Explained how blinding was maintained for the subject/parent/guardian. - Clarified that SRs were to be considered as being related to the product administered. Therefore, the assessment of causality by the Investigator was not required. - Described an additional data protection measures as per requirement from the European data privacy regulations; the purpose of the collection of race and ethnicity was to be defined in the study protocol and justified.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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